3.7 Given dose, attained concentrations and their importance
3.8.4 Proposed modification of dose regimen in children
In this study, compartmental pharmacokinetic models were developed for CQ and S in children ranging from 6 to 60 months in age. The population
pharmacokinetic model for CQ did not imply any correlation between body weight and age with the model parameters, while the S modeling results indicate an effect of body weight on the apparent central volume of distribution for the compound. The lack of covariate influence on CQ pharmacokinetics is an interesting finding and implies the current empirical age-based dosing to be irrational in this age range. Furthermore, these results suggest a weight-based dosing of S to be more appropriate than the current dosing based on age in children older than 6 months. Thus, the current practice to administer 50% lower doses at ages 6 - 24 months therefore seems sub-optimal. In a model where if all children were given the higher dose, only four children in the whole group would achieve S AUC0-336h values below the suggested cut-off value (12,000 μg*h/mL) for treatment response, and no child would have AUC0-336h values below the corresponding cut-off value (76 μg*h/mL) for CQ (Figure 5).
In proposing a dose modification, from a safety perspective it is important to avoid exceedingly high concentrations during the initial phase of dose intake, however, a strong relationship between high drug exposure of S and CQ and cure was found. And predicted Cmax levels after from the proposed dose modification showed that only three children relatively higher Cmax predictions, but not very different from some individuals given the current dosage regimen (IV). However, for countries where these drugs are still relatively efficacious,
these findings show that, response with CQ+SP combination can be improved by giving the higher dosage irrespective of body weight. Higher dosages of CQ (50mg/kg) [Kofoed et al, 2002; Sexton et al, 1988], and for SP (1000mg/50mg) [Barnes et al, 2206] have been previously proposed for improved outcomes in uncomplicated malaria. Therefore, in this study, a recommendation for children between 6 months to 24 months to be administered the higher dose regimen given to the older children can be done within safe Cmax limits to avoid any possible adverse effects (IV).
0 10 20 30 40 50 60 Age (months)
0 4000 8000 12000 16000 20000 24000 28000 32000 36000 40000 44000
AUC336 for SDx (ug*h/mL)
a) Sulfadoxine
0 10 20 30 40 50 60
Age (months) 0
20 40 60 80 100 120 140 160 180 200 220 240 260
AUC0-336 for CQ (ug*h/mL)
b) Chloroquine
Figure 5: Predicted AUC0-336 vs. age (a) for S and (b) for CQ if the higher Homapak dose had been administered to all children 6 months to 5 years.
Broken line depicts optimal cut-off value for AUC0-336 to predict treatment response.
3.9 CONCLUSSION
The fixed-dose chloroquine plus sulfadoxine/pyrimethamine formulation, locally known as Homapak, is of good quality with respect to CQ and S, but with the data on P lacking, it cannot unequivocally be said to be bioequivalent to the GMP products. There is no clinically relevant interaction between chloroquine,
sulfadoxine and pyrimethamine. The current dose regimen of half-strength Homapak to the younger children results in poor response. But treatment with AQ plus SP has superior efficacy against CQ plus SP combination. AQ could therefore be used as an alternative to CQ in combination with SP. Patient factor such as stunting and the given doses affect the pharmacokinetic parameters thus influencing the treatment outcomes with fixed-dose CQ+SP. A proposed dose modification to give the full-strength dose to all children in the age range 6 months to 5 years would improve treatment outcome with Homapak.
4 ACKNOWLEDGEMENTS
The work presented in this thesis has been made possible by the joint efforts of many people, some of whom I may not be able to mention by name, but to whom I remain for ever grateful for their selfless contributions. I would however like to thank most heartedly:
Assoc. Prof. Urban Hellgren, Department of Medicine, Unit of Infectious Diseases, Karolinska Institutet, who as my main tutor, gave so much in
friendship and personal time beyond just tutoring me in the design and conduct of clinical trial in this thesis. In you I never lacked academic and social support, both ingredients that made this thesis a success.
Prof. Lars L. Gustafsson, Division of Clinical Pharmacology, Karolinska Institutet, for instilling in me critical scientific values and perspectives in analyzing issues, and for your friendship and generosity while putting up with my difficult side, which surfaced from time to time, with the best lessons from you being - TTT (things take time), and never-ever-give-up.
Prof. Jasper W. Ogwal-Okeng, my Ugandan supervisor at Makerere University, for initiating the research plan and inviting me to participate in the collaborative clinical pharmacology research project with Swedish colleagues at the
Karolinska Institutet from which this thesis was a product. You have been a mentor and a very good friend.
Prof Elly Katunguka (Director) and Prof. Asibo Opuda (former Director) School of Graduate Studies, and Prof. Nelson Ssewankambo (Dean), Prof. Elly Katabira (Deputy Dean, Research), Faculty of Medicine, Makerere Universty for the encouragement and support that made it possible to complete this work.
I am grateful to Prof Anders Rane, the Head, Division of Clinical Pharmacology, Karolinska Institutet, and the entire administrative establishment of the Division, for the unreserved friendly welcome, support and encouragement that has been pivotal to the completion of this thesis.
My gratitude and thanks to Dr Paul Waako, Head, Department of Pharmacology and Therapeutics, and also Head, Clinical Pharmacology Sub-Program,
Makerere University – Karolinska Institutet joint degree program, for the many times you permitted my leave requests that availed me with the time to concentrate on completion of this thesis.
To Prof. Willy W. Anokbonggo, Emeritus professor of Pharmacology at Makerere University, for the advice and encouragement to pursue a PhD degree.
To Margarita Mahindi and Muhammad Ntale who dedicated a lot of time, with many challenges, in establishing the HPLC laboratory at the Department of Pharmacology and Therapeutics, Makerere University. I am particularly grateful to you for your tireless efforts in drug level analyses of the samples.
To Dr. Mia Lundblad (then a fellow PhD student at Karolinska Institutet) and Dr.Toufigh Jordi of the University of California, USA, for sharing their skills in PK
analysis and major contributions made in the pharmacokinetic modeling, calculations and analysis. Without your skills and in-put, I would have been at a loss during the PK analysis.
To Dr. Markus Jerling, for sparing time from you private work, to make me understand the world of pharmacokinetics modeling. Without your patience and humour, I would probably have had a tough time understanding population approach to PK studies. Of course I cannot forget the numerous working lunches that I enjoyed immensely, and the games we played with “Bouncy”, your friendly beautiful dog.
Dr. Max Petzold, Nordic School of Public Health, Göteborg, for being kind, generous and a wonderful host during my visits to Göteborg, and especially for sparing time to sit with me for hours trying to make sense of statistics.
I would like to thank all those who assisted during the conduct of the various studies, particularly Ms Judith Ayugi and Ms Peace Kobusinge of Makerere University for organizing the data collection. Ms Juliet Eyotaru, Senior Nursing Officer, Mulago Hospital and Dr. Quinto Ebony, Ms Jenifer Namuganza (Clinical Officer) and Mr. Wilson Nyegenye (Laboratory Technologist), Walukuba Health Center, Jinja, for their commitment and dedication during the field studies. And Mr. Sam Balikowa, for being such a dedicated and an accomplished malaria microscopist working tirelessly during the clinical study, for which I am truly grateful.
I am grateful to all the healthy volunteers and the sick children for participating in the studies. Your sacrifices made this thesis a reality.
And to the family of Urban (especially Birgit, Klaus, Eric and Sven), and the family of Lars (especially Katarina) for open heartedly welcoming me into your families and providing me with a home-a-way-from-home.
To all friends and colleagues on Plan 6 and 8, Division of Clinical Pharmacology, Karolinska Institutet for you cooperation and encouraging smiles. To all
colleagues at the Department of Pharmacology and Therapeutics, Makerere University, for all manner of support given to me during this work.
To Yvonne Sjölind and Margit Ekström, Departmental Secretaries, Division of Clinical Pharmacology, Karolinska Institutet, for your kindness and friendship, and especially to you Margit for always having a solution to any and every problem.
To my wife Maureen and our children Esther, Mario and Jocef for your constant prayers, love, perseverance and understanding.
I am very grateful for the generous funding of my studies by SIDA/SAREC (grants SWE– 1999 – 260, SWE – 2004 – 098, and SWE – 2005 – 030) through the Makerere University – Karolinska Institutet joint PhD-degree program. As one of the first candidates in the Clinical Pharmacology Sub-Program within this collaboration, I am very proud that this thesis is a product of a wonderful collaborative effort by Swedish and Ugandan senior researchers.
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